Alzheimer's disease (AD) is a neurodegenerative disease, and the diseases of over 90% of the AD patients are classified as sporadic Alzheimer's disease (sAD). Further, the AD patients show clinical features such as progressive loss of memory and other cognitive abilities. Pathologically, neuronal loss, glial proliferation, accumulations in the brain of intraneuronal neurofibrillary tangles and extracellular deposition of senile plaques primarily composed of β-amyloid protein (Aβ), are found in the AD brain [Selkoe, D. J. et al., Annu. Rev. Neurosci., 17, 489-517 (1994)]. Further, as other pathological characteristics, it has been known that an aberrant protein (PS2V) encoded by a variant of presenilin-2 gene is found in apoptotic pyramidal cells of each of cerebral cortex and hippocampal CA1 region of the sAD brain by immunohistochemical analysis [Sato, N. et al., J. Biol. Chem., 276, 2108-2114 (2001)].
PS2V has been known to be induced by hypoxic stimulation in cultured human neuroblastoma SK-N-SH cells [Sato, N. et al., J. Neurochem., 72, 2498-2505 (1999)]. Further, this hypoxia-induced PS2V is shown be dependent on a new protein synthesis in each of oxidative stress and SK-N-SH cells by using an antioxidant and cycloheximide [Sato et al. mentioned above, (1999)].
It has been known that a glucose-regulated protein (GRP78), which is endoplasmic reticulum (ER) stress-responsive molecular chaperone, is reduced by the above PS2V, and the production of β-amyloid protein is increased in PS2V-expressed cells [Sato, N. et al., J. Biol. Chem., 276, 2108-2114 (2001)].
However, although the possibility that PS2V is one of important factors for neuronal death has been suggested, the details of the mechanisms of the generation of PS2V and incidence of the disease have not been sufficiently known in the present situation.